Abstract Body

Neurons differ in their vulnerability to Alzheimer’s disease (AD). The basal forebrain cholinergic neurons are among the first to degenerate in AD. We have shown with longitudinal structural magnetic resonance imaging (sMRI) that abnormal basal forebrain degeneration (1) is detectable in cognitively normal older adults harboring preclinical cerebrospinal fluid concentrations of amyloid-β and phosphorylated tau, and (2) precedes and predicts cortical degeneration and cognitive impairment. While our initial findings hold promise for a novel preclinical AD biomarker, our current sMRI-based tools for measuring cholinergic neuronal integrity do not meet the clinical standard of sensitivity and specificity. The [18F] fluoroethoxy-benzovesamicol (FEOBV) radiotracer positron emission tomography (PET) holds promise for overcoming this obstacle. [18F] FEOBV binds to the vesicular acetylcholine transporter (VAChT), a glycoprotein involved in the transport of acetylcholine to synaptic vesicles in presynaptic terminals of cholinergic neurons. To date, the utility of [18F] FEOBV as a preclinical biomarker of AD pathology remains untested.

To accelerate development of the [18F] FEOBV radiotracer for routine use in clinical trials, drug discovery and clinical assessment, we have developed a novel mouse neuroimaging platform which integrates in vivo sMRI with and [18F] FEOBV PET to quantify the integrity of the cholinergic neurons in preclinical disease models. This platform provides critical benchmarks for calibrating the sensitivity and specificity of 18F] FEOBV PET to early disease-related changes in VAChT, enables high-throughput screening of preclinical pharmacological interventions, and is fully translatable to humans.